Gamma aminobutyric acid (“GABA”) is one of the major inhibitory neurotransmitters in the central nervous system of mammals. GABA regulates neuronal excitability through binding to specific membrane proteins (et al., GABAA receptor), which results in opening of an ion channel. Low levels of GABA have been observed in individuals suffering from epileptic seizures, motion disorders (e.g., multiple sclerosis, action tremors, tardive dyskinesia), panic, anxiety, depression, alcoholism and manic behavior. Therefore, it is of interest to develop GABA analogs, which have superior pharmaceutical properties in comparison to GABA.
A number of GABA analogs, with considerable pharmaceutical activity have been synthesized and described in the art (See, e.g., Satzinger et al., U.S. Pat. No. 4,024,175; Silverman et al., U.S. Pat. No. 5,563,175; Silverman et al., U.S. Pat. No. 6,028,214; Gallop et al. US 200400077553; Cundy, et al. U.S. Pat. No. 20050209319; Bryans, International Publication No. WO 00/31020; Bryans et al. WO 02/00209; Barret, et al. WO 05/027850; 04/089289). Among those synthesized GABA analogs, gabapentin, pregabalin, vigabatrin, and baclofen have been marketed and used to treat different disorder syndromes. For example, gabapentin and pregabalin are used to clinically treat, inter alia, epilepsy and neuropathic pain. The sales for gabapentin are higher than twenty millions.
One significant problem of the GABA analogs is the formation of toxic impurities such as gabapentin lactams during synthesis or formulating of GABA analogs. The amino group of GABA analogs can react with its carboxy functional group to form the gamma-lactam, which is more toxic than the GABA analog drug. For example, the toxicity of gabapentin (LD50, mouse) is more than 8000 mg/kg, while the corresponding lactam has toxicity (LD50, mouse) of 300 mg/kg. The high toxicity of the gamma-lactam structure results in serious difficulties in formulating GABA analogs and requires the addition of special purification steps to minimize the gamma-lactam contamination.
Rapid systemic clearance is another significant problem of many GABA analogs that are excreted by the kidney unmetabolized, thus requiring frequent dosing to maintain a therapeutic or prophylactic concentration in the systemic circulation (Bryans et al., Med. Res. Rev., 1999, 19, 149-177). For example, 300-600 mg of gabapentin single dose administered three times daily is typically used for anticonvulsive therapy. Higher doses (1800-3600 mg/day in divided doses) are typically used for the treatment of neuropathic pain states.
Employing a sustained release drug delivery system is a conventional solution to the problem of rapid systemic clearance of GABA analogs. However, the absorption efficiency in the colon and rectum for many GABA analogs, including gabapentin and pregabalin, is not as good as it is in the small intestine, where the GABA analogs are transported by the large neutral amino acid transporter (“LNAA”) (Jezyk et al., Pharm. Res., 1999, 16, 519-526). A successful application of sustained release technologies for many GABA analogs has been limited accordingly.
Thus, there is a need to develop a new GABA analog or a prodrug thereof, which is well absorbed from all parts of the intestine and for which sustained release technologies are applicable in resolving the above problems.